Spirocyclic compounds as innovative tools in drug discovery for medicinal chemists

Abstract

The occurrence of spirocyclic motifs in clinical candidates and approved drugs is on the rise. This is related to the improvement of drug-like properties that can be achieved by introducing this sp³-rich system into bioactive compounds. Given the increasing number of synthetic methodologies and building blocks available, spirocycles are becoming widely accessible to medicinal chemists. From restricting conformation to induce a better fit with the target, to modulation of physicochemical and pharmacokinetic properties, spirocycles are being used to address several challenges in drug discovery. This review covers general aspects of the chemistry of spirocycles, highlighting some key strategies for their preparation. As reported in publications over the past five years, we demonstrate that, beyond the exploration of structure-activity relationships (SAR) in medicinal chemistry, the use of spirocycles is an attractive approach for enhancing properties such as potency, selectivity, physicochemistry, and pharmacokinetics.

Keywords: Lipophilicity; Metabolic stability; Multiparametric optimization; Spatial configuration; hERG inhibition.